OVERALL PROGRAM SUMMARY One of the most significant challenges for understanding genetic control of blood pressure (BP) is that the vast majority of BP-associated single nucleotide polymorphisms (SNPs) in humans are located in noncoding regions of DNA. Many of these noncoding SNPs are located in haplotype regions thousands of base pairs away from any protein-coding gene and their effects on BP cannot be explained by any currently known coding or other functional sequence variant, making it nearly impossible to link these noncoding SNPs to genes or physiological pathways that regulate BP based on genomic sequence. Understanding the effect of intergenic noncoding SNPs on gene expression and the underlying mechanisms is a major challenge not just for BP and hypertension research, but for research on nearly all complex traits and common diseases. The goal of this PPG proposal is to begin to address this major challenge and test the overall hypothesis that noncoding SNPs associated with human BP but located far from any protein-coding gene regulate gene expression in specific BP relevant cell types through epigenetic mechanisms and these mechanisms can influence BP. We have developed three projects that each address one aspect of this overall hypothesis. Project 1 will use precision genome editing to identify the effect of specific BP- associated noncoding SNPs on gene expression in BP-relevant human cell types. Project 2 will test the hypothesis that BP-associated noncoding SNPs influence the expression of BP-relevant genes through epigenetic mechanisms including chromatin looping, enhancer function and noncoding RNA in human cells and tissues. Project 3 will take this line of research to animal models in vivo to test directly the novel hypothesis that chromatin conformation plays a role in BP regulation. The three projects will interact with, and inform, each other extensively and, together, will achieve the overall goal of the program. All three projects will rely on Core A for administrative support and Core B for sequencing coordination and data analysis. We have published at least 16 papers in the last few years that provide direct support for key aspects of the conceptual validity and technical feasibility of this PPG. In addition, we have obtained a large amount of preliminary data to further support the feasibility of the wide range of sophisticated and new technologies that we will use and the validity of proposed novel hypotheses. This PPG represents a fundamentally new direction for hypertension research. It will establish several novel approaches and technologies, generate unique and extensive datasets, and provide new biological insights, all of which will help to advance genetic and epigenetic research in hypertension and other disease areas.